Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

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Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer. / Read, Martin; Fong, Jim; Modasia, Bhavika; Fletcher, Alice; Imruetaicharoenchoke, Waraporn; Thompson, Rebecca; Nieto, Hannah; Reynolds, John; Bacon, Andrea; Mallick, Ujjal; Hackshaw, Allan; Watkinson, John; Boelaert, Kristien; Turnell, Andrew; Smith, Vicki; McCabe, Christopher.

In: Oncogene, 15.05.2017.

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@article{8d593e65684a4c7bb169bb914df5df6e,
title = "Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer",
abstract = "The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF andPTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4x10-4) compared to either PBF-(P=1.5x10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean GI index of 35.8±2.6%), as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA datasets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the RTK-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well-described to drive neoplastic growth. We also showed that overall survival (P=1.91x10-5) and disease-free survival (P=4.9x10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role inpromoting thyroid cancer that is predictive of poorer patient outcome.",
keywords = "DNA repair, DNA damage, p53, thyroid, PTTG1IP",
author = "Martin Read and Jim Fong and Bhavika Modasia and Alice Fletcher and Waraporn Imruetaicharoenchoke and Rebecca Thompson and Hannah Nieto and John Reynolds and Andrea Bacon and Ujjal Mallick and Allan Hackshaw and John Watkinson and Kristien Boelaert and Andrew Turnell and Vicki Smith and Christopher McCabe",
year = "2017",
month = may
day = "15",
doi = "10.1038/onc.2017.154",
language = "English",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

AU - Read, Martin

AU - Fong, Jim

AU - Modasia, Bhavika

AU - Fletcher, Alice

AU - Imruetaicharoenchoke, Waraporn

AU - Thompson, Rebecca

AU - Nieto, Hannah

AU - Reynolds, John

AU - Bacon, Andrea

AU - Mallick, Ujjal

AU - Hackshaw, Allan

AU - Watkinson, John

AU - Boelaert, Kristien

AU - Turnell, Andrew

AU - Smith, Vicki

AU - McCabe, Christopher

PY - 2017/5/15

Y1 - 2017/5/15

N2 - The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF andPTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4x10-4) compared to either PBF-(P=1.5x10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean GI index of 35.8±2.6%), as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA datasets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the RTK-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well-described to drive neoplastic growth. We also showed that overall survival (P=1.91x10-5) and disease-free survival (P=4.9x10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role inpromoting thyroid cancer that is predictive of poorer patient outcome.

AB - The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF andPTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4x10-4) compared to either PBF-(P=1.5x10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean GI index of 35.8±2.6%), as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA datasets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the RTK-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well-described to drive neoplastic growth. We also showed that overall survival (P=1.91x10-5) and disease-free survival (P=4.9x10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role inpromoting thyroid cancer that is predictive of poorer patient outcome.

KW - DNA repair

KW - DNA damage

KW - p53

KW - thyroid

KW - PTTG1IP

U2 - 10.1038/onc.2017.154

DO - 10.1038/onc.2017.154

M3 - Article

JO - Oncogene

JF - Oncogene

SN - 0950-9232

M1 - 72326

ER -